The primary objective of this project is to develop new drugs which will be useful in the treatment of hyperlipoproteinemic diseases and produce beneficial endothelial and smooth muscle changes which may reduce the development of atherosclerotic plaque formation. For these reasons, novel cyclic clofibrate-related analogs, previously synthesized in our laboratories, will be tested in normal, sucrose- and high-fat-glycerol fed rats for their antilipidemic and antilipolytic properties. Following these studies selected analogs will be subjected to several mechanistic investigations to assess their effects on catabolism and anabolism of cholesterol, triglycerides, and plasma lipoproteins, their actions on the hormone sensitive triglyceride lipase system, on lipoprotein transport across the endothelium, and on their ability to modify esterifying and hydrolytic enzyme activities involved in the metabolism of cholesterol and cholesterol esters in arterial tissues. A modification of platelet function will also be determined as an assessment of the anti-aggregatory properties possessed by these analogs. Analog modification of metabolic and hormonal control systems will be monitored in liver and plasma; biotransformation and drug distribution will be determined in order to relate drug tissue localization to the observed modification of endocrine response and/or activities of specific enzyme systems located within the hepatocyte. These studies, in vivo and in vitro, are expected to advance our knowledge on mechanism and selective action of antilipidemic drugs and provide a basis for rational drug development.